DESCRIPTION: MinK is a small ion channel subunit with a single transmembrane span. It is active only after assembly with a pore-forming subunit. Nonetheless, MinK is required for normal channel function in some tissues. Last period we learned why: MinK determines the gating kinetics, unitary conductance, ion selectivity, regulation and pharmacology of these mixed channel complexes. In the heart and ear, Mink assembles with KCNQ1 to form Iks channels. Inherited Mink mutations are associated with altered IKs function, cardiac arrhythmia and deafness. Mink was thought to be unique until last year when we cloned 3 genes encoding Mink-related peptides (MiRPs). In the last period, we studied the function, dysfunction and structure/function of MinK. We learned how disease-associated mutations altered Mink function and identified residues critical for activity. This allowed isolation of the genes for MiRP1, MiRP2 and MIRP3. We then found that MiRP1 assembled with the pore-forming subunit HERG to reconstitute attributes of cardiac IKr channels. This led to our identification of MIRP1 mutations associated with sporadic long QT syndrome (LQTS), a rare disorder that predisposes to sudden death. More significantly, we later discovered that a MiRP1 polymorphism present in approximately 1.6 percent of healthy individuals places this large group at risk for a common, life-threatening disorder: drug-induced LOTS. Our most recent studies reveal that MiRPs operate not only with KCNQ1 and HERG but also with classical voltage-gated potassium channel subunits throughout the body. The central goal of this application arises directly from our studies of Mink over the last five years: we seek to learn how M1RPs (including Mink) operate in normal and disease states. The four specific aims are designed to evaluate (1) newly identified native MiRP-partner complexes from skeletal muscle, heart and brain; (2) newly identified disease-associated mutants; (3) MiRP domains and residues that mediate channel function; and, (4) sites of contact in MiRP-partner complexes. We argue these small subunits merit intense scrutiny. First, they are important to normal physiology and disease pathogenesis. Second, they have potential to reveal mechanisms of ion channel function from a unique vantage point: a peptide intimate with (but not of) the pore-forming subunit.